Recently, small interfering RNA (siRNA) technology has emerged as a remarkable therapeutic tool for sequence specific targeted silencing of genes and now is considered as a novel class of therapeutics for molecular therapy of cancer. This technology offers the potential of hitting targets that are currently inaccessible or undrugabble by conventional small-molecule inhibitors, antibodies or larger drugs. Despite being amongst the most common oncogenes in human cancers and present in about 90% of PDAC cases, to date mutated KRAS oncogene has not been effectively targeted and clinical options for inhibiting its activity still remains to be developed. To meet this challenge, we recently developed novel long-acting slow release nanoparticle platforms including, 1) Stealth Liposomal Nanoparticles (SLNP) and 2) Dual- Assembly Nanoparticles (DANPs) can target siRNA into in vivo tumors and robustly silence target genes up to 2 weeks after a single injection. We identified KRAS siRNA sequences with notable potency in knocking-down KRAS expression (>90%) in several in vivo tumor models. AXL-RTK is widely expressed by PDAC by AXL-aptamer coated long-acting NPs incorporating KRAS siRNA will provide dual function and antitumor effect by increasing uptake and providing addition therapeutic effect for PDAC. Our central hypothesis is effective knockdown of mutant KRAS by highly versatile long-acting tumor-cell targeted siRNA nanotherapeutics will enhance the uptake, provide robust gene silencing and have a significant dramatic impact tumor growth due to dual antitumor/metastatic effect. Our long-term goal is to develop safe and effective tumor-targeted therapeutic siRNA-therapeutics for the molecular targeting of KRAS. Overall these studies may provide the proof-of-concept for targeting KRAS with cancer. Because our novel nanoplatforms for delivering siRNA-therapeutics were very reliable and safe in mice, thus this approach can be easily translated into Phase I Clinical Trials for BC patients. Our goal in this project is to develop clinically applicable, safe and effective nanotherapeutic tools to achieve robust and prolonged KRas silencing and demonstrate antitumor efficacy in in preclinical models that mimic human disease.